Development and verification of a pharmacokinetic model to optimize physiologic replacement of rhIGF-1/rhIGFBP-3 in preterm infants.

BACKGROUND: rhIGF-1/rhIGFBP-3 is being investigated for prevention of retinopathy of prematurity in extremely preterm infants. METHODS: A population pharmacokinetic model was developed using data from phase I/II (Sections A-C) trials of rhIGF-1/rhIGFBP-3 and additional studies in preterm infants to predict optimal dosing to establish/maintain serum IGF-1 within physiological intrauterine levels. In Section D of the phase II study, infants (gestational age (GA) (wk+d) 23+0 to 27+6) were randomized to rhIGF-1/rhIGFBP-3, administered at the model-predicted dose of 250 µg/kg/d continuous i.v. infusion up to postmenstrual age (PMA) 29 wk+6 d or standard of care. An interim pharmacokinetic analysis was performed for the first 10 treated infants to verify dosing. RESULTS: Serum IGF-1 data were reviewed for 10 treated/9 control infants. Duration of therapy in treated infants ranged 1-34.5 d. At baseline (before infusion and <24 h from birth), mean (SD) IGF-1 was 19.2 (8.0) µg/l (treated) and 15.4 (4.7) µg/l (controls). Mean (SD) IGF-1 increased to 45.9 (19.6) µg/l at 12 h in treated infants, and remained within target levels for all subsequent timepoints. For treated infants, 88.8% of the IGF-1 measurements were within target levels (controls, 11.1%). CONCLUSION: Through the reported work, we determined appropriate rhIGF-1/rhIGFBP-3 dosing to achieve physiological intrauterine serum IGF-1 levels in extremely preterm infants.

The High Direct Medical Costs of Prader-Willi Syndrome.

OBJECTIVE: To assess medical resource utilization associated with Prader-Willi syndrome (PWS) in the US, hypothesized to be greater relative to a matched control group without PWS. STUDY DESIGN: We used a retrospective case-matched control design and longitudinal US administrative claims data (MarketScan) during a 5-year enrollment period (2009-2014). Patients with PWS were identified by Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code 759.81. Controls were matched on age, sex, and payer type. Outcomes included total, outpatient, inpatient and prescription costs. RESULTS: After matching and application of inclusion/exclusion criteria, we identified 2030 patients with PWS (1161 commercial, 38 Medicare supplemental, and 831 Medicaid). Commercially insured patients with PWS (median age 10 years) had 8.8-times greater total annual direct medical costs than their counterparts without PWS (median age 10 years: median costs $14 907 vs $819; P < .0001; mean costs: $28 712 vs $3246). Outpatient care comprised the largest portion of medical resource utilization for enrollees with and without PWS (median $5605 vs $675; P < .0001; mean $11 032 vs $1804), followed by mean annual inpatient and medication costs, which were $10 879 vs $1015 (P < .001) and $6801 vs $428 (P < .001), respectively. Total annual direct medical costs were ∼42% greater for Medicaid-insured patients with PWS than their commercially insured counterparts, an increase partly explained by claims for Medicaid Waiver day and residential habilitation. CONCLUSION: Direct medical resource utilization was considerably greater among patients with PWS than members without the condition. This study provides a first step toward quantifying the financial burden of PWS posed to individuals, families, and society.

A randomized prospective study of insulin pump vs. insulin injection therapy in very young children with type 1 diabetes: 12-month glycemic, BMI, and neurocognitive outcomes.

OBJECTIVE: To compare glycemic control, body mass index (BMI), neurocognitive function, and parenting stress for preschool-aged diabetic children randomized to treatment either with continuous subcutaneous insulin infusion (CSII) or with intensive insulin injection therapy (IIT). METHODS: Children <5 yr of age diagnosed with type 1 diabetes mellitus for at least 12 months were randomized to either CSII (n = 21) or IIT (n = 21) for 6 months. After 6 months, the IIT group began CSII therapy and the CSII group continued on pumps. Hemoglobin A1c (HbA1c) and BMI percent were collected at baseline, 3, 6, 9, and 12 months. Neurocognitive assessments (Developmental Test of Visual-Motor Integration and Stanford-Binet Intelligence Scale: Fourth Edition) were administered to children, and parenting and child behavior assessments (Parenting Stress Index and Child Behavior Checklist) were completed by parents and at baseline, 6, and 12 months. RESULTS: Thirty-five children completed the study. Mean HbA1c decreased significantly over the study period (8.9% +/- 0.6 vs. 8.5% +/- 0.7, p = 0.006). Initiation of CSII resulted in an HbA1c decrease of 0.4% after 3 months (p = 0.002); however, in the CSII first group, the HbA1c at 12 months was not significantly different from study start (8.8% +/- 0.6 vs. 8.5% +/- 0.6; p = 0.4). There were no significant changes in BMI%, neurocognitive, parenting, and child behavior measures between groups. CONCLUSION: Initiation of CSII vs. continuing IIT does not significantly influence HbA1c, BMI, neurocognitive, or parenting stress parameters in a research study setting.

Issues and trends in pediatric growth hormone therapy--an update from the GHMonitor observational registry.

The GHMonitor observational registry collates data on pediatric subjects receiving Saizen (recombinant human growth hormone (GH)) therapy. From January 2003 through August 2006, 1335 subjects were enrolled in the registry, approximately two-thirds of whom are male. The most common diagnosis in the registry is idiopathic growth hormone deficiency (58%). Most subjects in GHMonitor are receiving Saizen doses using a needle-free delivery device, the cool.click (73%). Mean height standard deviation scores show an improvement from -2.1 at screening to -1.1 following 3 years of Saizen therapy. To date, adverse events have been reported in 4% of subjects. Three serious adverse events were identified to be related to Saizen by the primary investigator: cellulitis at the injection site, behavioral problems/suicidal ideation, and enlargement of a craniopharyngioma. This article provides an update on data from the registry and briefly discusses topical and controversial issues in the treatment of pediatric patients requiring GH therapy.

Continuous longitudinal infusion of rhIGF-1/rhIGFBP-3 in extremely preterm infants: Evaluation of feasibility in a phase II study.

OBJECTIVE: To evaluate the feasibility of continuous longitudinal intravenous infusion of recombinant human insulin-like growth factor-1/recombinant human insulin-like growth factor binding protein-3 (rhIGF-1/rhIGFBP-3) for prevention of retinopathy of prematurity and other complications in extremely preterm infants (<28weeks' gestational age), based on initial sections of a phase II randomized controlled trial. DESIGN: The phase II trial was designed in four sections (A-D); we report pharmacokinetic and adverse events (AEs) data pooled for Sections B and C. Infants in these study sections received rhIGF-1/rhIGFBP-3 or standard neonatal care up to postmenstrual age (weeks+days) 28+6 (Section B) or 29+6 (Section C). Dosing was variable/individualized and intended to establish serum IGF-1 within physiological intrauterine levels. RESULTS: Nineteen infants were enrolled across Sections B/C: nine received rhIGF-1/rhIGFBP-3 and 10 standard neonatal care. Among the nine infants treated with study drug, mean (SD) dose was 95.1 (10.6)µg/kg/day and mean (SD) duration of infusion was 14.2 (6.1)days. Eight of nine (88.9%) treated infants had two or more dose changes during treatment. Mean serum IGF-1 levels during treatment were 23µg/L among treated infants compared with 14µg/L in control infants. Overall, 66.3% of IGF-1 measurements for treated infants were within target levels (20-60µg/L) versus 17.3% for control infants. Overall incidence of adverse events (AEs) was similar for treated versus control infants; AEs were generally as expected in this population, and no AEs were considered related to study treatment. There was no observed increase in infection rates (considered a possible risk with continuous intravenous infusion) between treated and control infants. Rates of hypoglycemia (considered a possible risk with IGF-1 treatment) were also similar between groups. There was one fatal serious AE of cardiac tamponade in the treated group (not considered treatment related). CONCLUSION: Infusion of rhIGF-1/rhIGFBP-3 increased serum concentrations of IGF-1 and attainment of target levels relative to standard neonatal care. rhIGF-1/rhIGFBP-3 infusion was well tolerated with no safety signals. Although further work is required to optimize the dose regimen for attainment of physiological intrauterine levels, we believe the results reported support the feasibility of rhIGF-1/rhIGFBP-3 continuous longitudinal infusion in extremely preterm infants. The trial is registered at ClinicalTrials.gov (NCT01096784).

Treatment of familial male-limited precocious puberty with bicalutamide and anastrozole.

This report describes the use of bicalutamide and anastrozole in two subjects with familial male-limited precocious puberty. Clinical improvements include decreased facial acne and pubic hair. Most importantly, a marked decrease in growth velocity and skeletal advancement has been achieved.

The use of tamoxifen to improve height potential in short pubertal boys.

A retrospective chart review of 7 pubertal boys who were treated with tamoxifen was conducted to determine the effects of this therapy on skeletal maturation and predicted adult height. Tamoxifen significantly decreased the rate of skeletal maturation and increased the predicted adult height without negative effects on sexual maturation. Additional evaluation of this therapy is now required to determine if the increase in predicted adult height results in a clinically significant increase in final adult height.

Hashitoxicosis in children: clinical features and natural history.

OBJECTIVE: To determine the incidence, natural history, and clinical characteristics of Hashitoxicosis (Htx) in pediatric patients with autoimmune thyroiditis. STUDY DESIGN: Medical records of children diagnosed with Hashimoto thyroiditis between 1993 and 2002 were reviewed. The clinical course of patients presenting with hyperthyroidism was determined. Variables including sex, age, family history, thyroid hormone levels, anti-thyroid antibody titers, 123 I thyroid scan results, and presenting features were investigated as possible predisposing factors for the development of Htx. RESULTS: Out of 69 patients with autoimmune thyroiditis, 8 were diagnosed with Htx. The duration of hyperthyroidism ranged from 31 to 168 days. Three patients became hypothyroid after an average of 46.3 +/- 13.2 days, and 5 patients became euthyroid after an average of 112.8 +/- 59.8 days. Additional findings included an elevated thyroid stimulating immunoglobulin (TSI) titer in 3 of the 8 patients with Htx, and increased uptake on 123 I scan in 2 patients. CONCLUSION: Htx is an uncommon yet important cause of hyperthyroidism in children that has a variable clinical course. The diagnosis may be complicated, as presenting features sometimes exhibit significant overlap with Graves' disease. No factors predisposing to the development of Htx were identified.

Infant with classic congenital adrenal hyperplasia (CAH) born to a mother with classic CAH.

We report a female infant with classic congenital adrenal hyperplasia (CAH), secondary to 21-hydroxylase deficiency, who was born to a mother with salt-wasting CAH.